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Relevant academic research and scientific papers

New 8-aminoalkyl derivatives of purine-2,6-dione with arylalkyl, allyl or propynyl substituents in position 7, their 5-HT1A, 5-HT2A, and 5-HT7 receptor affinity and pharmacological evaluation

Background: Our previous studies in a group of arylpiperazine derivatives of 1,3-dimethyl-3,7-dihydro-purine-2,6-diones, aimed at chemical diversification of the purine-2,6-dione by introduction of hydrophobic substituent in a 7- or 8- position or elongation of the linker length between arylpiperazine and purine core, allowed a selection of potent 5-HT1A, 5-HT2A and 5-HT7 receptor ligands displaying anxiolytic and antidepressant properties. Continuing our research in this field, in the present studies we designed a new series of 8-aminoalkylamino (15-35) and 8-arylpiperazinylpropoxy (36-42) derivatives of 7-substituted 1,3-dimethyl-3,7-dihydropurine-2,6-dione as potential 5-HT1A, 5-HT2A and 5-HT7 receptor ligands with potential psychotropic activity. Methods: Radioligand binding assays were employed for determining the affinity and the selectivity profile of the synthesized compounds for native 5-HT1A, 5-HT2A, and cloned 5-HT6 and 5-HT7 receptors. The functional activity of the selected compounds at 5-HT1A and 5-HT2A receptors was tested in the commonly used in vivo models. Antidepressant and anxiolytic properties were evaluated in the forced swim (FST) and the four-plate test (FPT) in mice, respectively. Results: Among the evaluated series, selected 7-benzyl-8-((4-(4-(3-chlorophenyl)piperazin-1-yl)butyl)amino)-1, 3-dimethyl-1H-purine-2,6(3H,7H)-dione (21), a mixed 5-HT1A/5-HT 2A/5-HT7 receptor ligand, produced an antidepressant-like effect in FST, and exerted anxiolytic-like activity in FPT. Another pharmacologically evaluated compound 42 (a mixed 5-HT1A/5-HT 7 ligand) slightly, but non-significantly attenuated the immobility time of mice in FST and was devoid of activity in FPT. Conclusions: Study revealed advantage of mixed 5-HT1A/5-HT2A/5-HT7 receptor ligands over 5-HT1A/5-HT7 agents to display antidepressant-and anxiolytic-like activity. Modification of arylalkyl/allyl substituent in position 7 of purine-2,6-dione opens possibility for designing new 5-HT ligands with preserved p electron system and lower molecular weight. Copyright

Structure and activity studies of glycine receptor ligands. Part 4. N-[(7-arylalkyl,7-aryloxyalkyl)-8-theophyllyl]-glycines

Preparation of N-[(7-arylalkyl,7-aryloxyalkyl)-8-theophyllyl]-glycines by condensation of 8-bromo-theophylline with arylalkyl-and aryloxyalkylbromides and aminolysis with glycine is described. The structure of one of the obtained glycine derivatives was confirmed by X-ray analysis. A comparison of the glycine receptor binding model (molecule L-689,560) and the 3-D structure of that molecule indicates serious differences in molecule shape, explaining their inactivity.